Acquired immune deficiency syndrome (AIDS) is characterized by immunosuppression which predisposes patients to opportunistic infections and certain unusual forms of neoplasms. This syndrome was first recognized as a clinical entity in 1981 (Gottlieb et al., (1981) Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of new acquired cellular immunodeficiency. New Engl J Med 305:1425-1431; Masur et al., (1981) An outbreak of community-acquired pneumocystic carinii pneumoniae: initial manifestation of cellular immune dysfunction. New Engl J Med 305:1431-1438; Siegal et al., (1981) Severe acquired immunodeficiency in male homosexuals, manifested by chronic perional ulcerative herpes simplex lesion. New Engl J Med 305:1439-1444). In 1984, a human retrovirus, HIV-1, was found to be the cause of AIDS (Barre-Sinoussi et al., (1983) Isolation of a Tlymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome. Science 220:868-871; Gallo et al., (1984) Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre AIDS. Science 224:500-503; popovic et al., (1984) Detection, isolation and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224:497-500). Human immunodeficiency virus (HIV-1) preferentially infects and destroys CD4-positive T-cells. After the discovery of the HIV-1, efforts were directed towards finding drugs which would be effective as anti-HIV agents. Several chemical agents, including interferon, have been tested for their therapeutic potential against HIV-1 (Ho et al., (1985) Recombinant human interferon alpha-A suppresses HTLV-III replication in vitro. Lancet i:602-604; McCormick et al., (1985) Ribavirin suppresses replication of lymphadenopathy associated virus in cultures of human adult T-Lymphocytes. Lancet ii:1367-1369; Mitsuya et al., (1985) 3'-azido-3'-deoxythymidine (BWA509H): an antiviral agent that inhibits the infectivity and cytopathic effect of human-T-lymphotrophic virus type III in vitro. Proc Natl Acad Sci USA 82:7096-7100; Narashima et al., (1986) Inhibition of T-cell lymphotropic virus type III by 3'-azido-3'-deoxythymidine in vitro. Antimicrob Agents Chemother 30:933-937; Anand et al., (1988) Interaction between rifabutin and human immunodeficiency virus type-1; inhibition of replication, cytopathic effect and reverse transcriptase in vitro. Antimicrob Agents Chemother 32:684-688). The dideoxynucleosideanalogue3'-azido-2',3'-dideoxythy-midine (AZT) was found to be very efficacious in inhibiting the infectivity and cytopathic effect of HIV-1 in vitro (Mitsuya et al., (1985) 3'-azido-3'-deoxythymidine (BWA509H): an antiviral agent that inhibits the infectivity and cytopathic effect of human-T-lympho-trophic virus type III in vitro. Proc Natl Acad Sci USA 82:7096-7100; Mitsuya et al., (1987) Rapid in vitro systems for assessing activity of agents against HTLV-III/LAV. In AIDS: Modern Concepts and Therapeutic Challenges. Broder, S. (ed.). New York: Marcel Dekker, 303-333). AZT has been shown to increase the survival and decrease the frequency of opportunistic infections in certain patients with AIDS and AIDS-related complex (ARC) (Yarchoan et al., (1988) Phase 1 studies of 3',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Kabcetm 1:76-80). AZT, however, is associated with toxicities that limit its use, particularly bone marrow suppression with megaloblastic changes though the decline in CD4-positive cells has been delayed in patients who have been taking AZT for prolonged periods (Richman et al., (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. New Engl J Med 317:192-197; Yarchoan et al., (1988), supra; Yarchoan et al., (1989) In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science 245:412-415). In 1988, AZT-resistant strains of HIV were isolated from patients (Larder et al., (1989) HIV with reduced sensitivity to Zidovudine (AZT) isolated during prolonged therapy. Science 243:1731-1734).
Recently, it was shown that dextran sulphate (DS) has anti-HIV activity and acts synergistically with AZT (Ito et al., (1989) Inhibitory effect of dextran sulfate and heparin on the replication of human immunodeficiency virus in vitro. Antiviral Res 7:361-367; Ueno and Kuno, (1987) Dextran sulfate, a potent anti-HIV agent in vitro having synergism with Zidovudine. (Letter.) Lancet i:1379). Pentosan polysulfate, PPS, like DS, is a negatively charged polysaccharide but has a lower molecular weight (4000 for PPS;&gt;6000 for DS). PPS has been reported to increase the number of circulating T-cells in a subset of migraine patients who have low basophil and T-cell concentration (Thonnard-Neuman and Neckers, (1981) T-lymphocytes in migraine. Ann Allerg 47:325-327; Thonnard-Neuman and Bigelow, (1988) Prophylaxis of migraine with anionic polyelectrolytes. Headache zs:114-120). PPS has also been shown to have low anticoagulant activity (Soria et al., (1980) Anticoagulant activities of a pentosane polysulphate: comparison with standard heparin and function of low molecular weight heparin. Thromb Res 19:455-463; Vinazzer et al., (1980) Influence on the clotting mechanism of sodium pentosan polysulphate (SP-54) in comparison to commercial beef lung sodium heparin. Thromb Res 20:57-68; Baba et al., (1988) Pentosan polysulfate, a sulfated oligosaccharide is a potent and selective anti-HIV agent in vitro. Antiviral Res 9:335-343). In fact, it has been reported that PPS achieves its anti-HIV-1 activity at a concentration 370-fold below its anti-coagulant threshold (Baba et al., (1988), supra. .varies.-cyclodextrin sulphate ("A-CDS") and .beta.-cyclodextrin sulphate ("B-CDS") are cyclical sulphated polysaccharides (Pitha et al., (1988) Drug solubilizers to aid pharmacologists: amorphous cycledextrin derivatives. Life Sci 43:493-502; Pitha, (1989) Pitha, J. (1989) Cyclodextrins: Solutions to Insolubility. Neurotransmissions. V 1-4. Natiok, MA: Research Biochemical Incorporated) whereas PPS is a sulphated polysaccharide with linear configuration (Pentosan PoIysuIfate (SP-54) Basic Information, published by bene-Arzeneimittel GmbH, Munchen 71, Germany, Mar., 1985). Thus, there is a great need for alternative drugs and combination therapies. The present invention has been accomplished with the above concerns in mind.